Adenosine acts through A2 receptors to inhibit IL-2-induced tyrosine phosphorylation of STAT5 in T lymphocytes: role of cyclic adenosine 3',5'-monophosphate and phosphatases - PubMed (original) (raw)

Adenosine acts through A2 receptors to inhibit IL-2-induced tyrosine phosphorylation of STAT5 in T lymphocytes: role of cyclic adenosine 3',5'-monophosphate and phosphatases

Hong Zhang et al. J Immunol. 2004.

Abstract

Adenosine is a purine nucleoside with immunosuppressive activity that acts through cell surface receptors (A(1), A(2a), A(2b), A(3)) on responsive cells such as T lymphocytes. IL-2 is a major T cell growth and survival factor that is responsible for inducing Jak1, Jak3, and STAT5 phosphorylation, as well as causing STAT5 to translocate to the nucleus and bind regulatory elements in the genome. In this study, we show that adenosine suppressed IL-2-dependent proliferation of CTLL-2 T cells by inhibiting STAT5a/b tyrosine phosphorylation that is associated with IL-2R signaling without affecting IL-2-induced phosphorylation of Jak1 or Jak3. The inhibitory effect of adenosine on IL-2-induced STAT5a/b tyrosine phosphorylation was reversed by the protein tyrosine phosphatase inhibitors sodium orthovanadate and bpV(phen). Adenosine dramatically increased Src homology region 2 domain-containing phosphatase-2 (SHP-2) tyrosine phosphorylation and its association with STAT5 in IL-2-stimulated CTLL-2 T cells, implicating SHP-2 in adenosine-induced STAT5a/b dephosphorylation. The inhibitory effect of adenosine on IL-2-induced STAT5a/b tyrosine phosphorylation was reproduced by A(2) receptor agonists and was blocked by selective A(2a) and A(2b) receptor antagonists, indicating that adenosine was mediating its effect through A(2) receptors. Inhibition of STAT5a/b phosphorylation was reproduced with cell-permeable 8-bromo-cAMP or forskolin-induced activation of adenylyl cyclase, and blocked by the cAMP/protein kinase A inhibitor Rp-cAMP. Forskolin and 8-bromo-cAMP also induced SHP-2 tyrosine phosphorylation. Collectively, these findings suggest that adenosine acts through A(2) receptors and associated cAMP/protein kinase A-dependent signaling pathways to activate SHP-2 and cause STAT5 dephosphorylation that results in reduced IL-2R signaling in T cells.

PubMed Disclaimer

Cited by

Advances in macrophage and T cell metabolic reprogramming and immunotherapy in the tumor microenvironment.
Cheng H, Zheng Y. Cheng H, et al. PeerJ. 2024 Jan 15;12:e16825. doi: 10.7717/peerj.16825. eCollection 2024. PeerJ. 2024. PMID: 38239299 Free PMC article.
A novel VIP signaling pathway in T cells cAMP-->protein tyrosine phosphatase (SHP-2?)-->JAK2/STAT4-->Th1 differentiation.
Liu L, Yen JH, Ganea D. Liu L, et al. Peptides. 2007 Sep;28(9):1814-24. doi: 10.1016/j.peptides.2007.03.015. Epub 2007 Mar 31. Peptides. 2007. PMID: 17462790 Free PMC article.
Forskolin-inducible cAMP pathway negatively regulates T-cell proliferation by uncoupling the interleukin-2 receptor complex.
Rodriguez G, Ross JA, Nagy ZS, Kirken RA. Rodriguez G, et al. J Biol Chem. 2013 Mar 8;288(10):7137-46. doi: 10.1074/jbc.M112.408765. Epub 2013 Jan 22. J Biol Chem. 2013. PMID: 23341462 Free PMC article.
Integrated multiomics revealed adenosine signaling predict immunotherapy response and regulate tumor ecosystem of melanoma.
Xu Y, Lau P, Chen X, Zhao S, He Y, Jiang Z, Chen X, Zhang G, Liu H. Xu Y, et al. Hum Genomics. 2024 Sep 15;18(1):101. doi: 10.1186/s40246-024-00651-3. Hum Genomics. 2024. PMID: 39278925 Free PMC article.
The adenosinergic machinery in cancer: In-tandem insights from basic mechanisms to therapy.
Kang C, Liu L, Wu C, Li L, Jia X, Xie W, Chen S, Wu X, Zheng H, Liu J, Li R, Zeng B. Kang C, et al. Front Immunol. 2023 Feb 23;14:1111369. doi: 10.3389/fimmu.2023.1111369. eCollection 2023. Front Immunol. 2023. PMID: 36911717 Free PMC article. Review.

Adenosine acts through A2 receptors to inhibit IL-2-induced tyrosine phosphorylation of STAT5 in T lymphocytes: role of cyclic adenosine 3',5'-monophosphate and phosphatases - PubMed (original) (raw)